Androgenic composition



Patented June 10, 1952 ANDROGENIO COMPOSITION Clarence T. Van Meter, Arlington, N. J., assignor to Reed & Carnrick, Jersey City, N. J a corporation of New J ersey No Drawing. Application September 18, 1948, Serial No. 50,012

1 3 Claims.

This-invention relates to an improved method for the parenteral administration, of testosterone, testosterone derivatives and other androgenic materials for therapeutic purposes.

Testosterone, testosterone derivatives and other androgenic materials have been administered parenterally for therapeutic purposes in a variety of ways. One method consists in injecting a solution of the medicament in a suitable oil such as that of corn, peanut or sesame, This method has the following chief disadvantages: (a) it occasionally results in an undesirable, yet natural, walling-01f of the injected oil globule thus giving rise to an oil embolism which retards, or in some cases even completely inhibits, the desired physiological absorption of the medicament, and also impairs normal fluid movement through and be tween tissues adjacent to the site of the embolism; (b) the androgenic solute is comparatively easily absorbed from such a solution with the result that the physiological action is undesira'bly transient rather than prolonged, thus ne= cessitating an objectionable increase in the frequency of injections required to obtain optimum therapeutic results; the oily character of such a preparation creates a special problem with respect to the cleaning and sterilizing of hypodermic equipment.

A second method for the parenteral administration of androgenic materials consists in the implantation of a pallet of the active substance in a cavity especially prepared for receiving it by surgical means. In addition to demanding a certain amount of skill on the part of the operator, this method of administration possesses the further disadvantages: (a) that the patient is exposed to the risk of infection involved in the prep aration of the cavity, and (b) that such an implant is not infrequently so thoroughly and efficiently encapsulated by one or another of natures mechanisms of dealing with foreign insoluble bodies that the desired continuous absorption and the resultant continuous therapeusis are seriously inhibited and often completely prevented.

A third method of administering androgenic materials consists in the injection of a suspension of the medicament dispersed in a liquid in which it is comparatively insoluble. While prolonged action issometimes secured in this manner, nevertheless the method is characterized by several disadvantages, particularly: (a) the precision with which the suspension must be prepared if the individual particles are to be of uniform and proper size in order to permit uniform and prolonged physiological utilization, (b) the difficulties attendant the preparation of such a product with positive assurance that it is free of contamination with insoluble foreign particles, (0) problems associated with rendering such a product absolutely sterile by processes which will not .cause a change in size of the suspended particles, and (d) the care which must be exercised by the technician if uniform doses are to be continuously withdrawn from multidose vials.

A fourth method of administering androgenic materials is by injecting a true solution of the medicament in a physiologically-inert, watermiscible solvent such as propylene glycol and glycerin. This method is disadvantageous in that: (a) greater dilution with tissue fluid is required in case quantitative precipitation of the medicament is desired, (12) the particles of medicament which precipitate on dilution of such solution are not uniform in size thus making impossible uniform physiological absorption from the individual particles, and (c) such solutions are commonly hygroscopic in character and give rise to irritational efiects on administration, presumably through their property of abstracting water from adjacent tissues. 7

The main object of this invention is toprovide a new and novel method of administering testosterone and other androgenically active materials whereby the previously described disadvantages associated with methods of administration in current use are overcome.

In general, the novel method of administration herewith invented consists in the preparation of a solution of the androgenic material in a specially constructed vehicle, the finished solution being such that when injected, dilution with tissue fluid soon causes a practically quantitative precipitation of the testosterone or other androgenic material in macroscopically uniform particles. The specially constructed vehicle is composed of two parts: (1) a physiologically-inert, water-miscible organic solvent for the androgenic material such as propylene glycol, diluted with water if necessary to obtain optimal precipitation characteristics on further dilution with tissue fluid, and (2) a physiological-inert solute such as a polyoxyalkylene sorbitan monolaurate in an amount suflicient to regulate the precipitation characteristics of the solution so that on dilution with tissue fluid the testosterone or other androgenic'material is precipitated in particles of uniform size.

By varying the concentration of the precipitation regulator in relation to the concentration of the androgenic material, the timerequired for precipitation of the androgenic material when the solution is diluted can be varied within wide limits, thus making possible the preparation of products which will precipitate quickly in a limited region near the site of injection or products which will precipitate more slowly over a more extended region.

While the. advantages inherent in the novel method of administration provided by this invention can be deduced from the hereinbefore given description of the disadvantages characteristic of the ordinary methods of administration in current use, nevertheless, forconvenience'these ad vantages are specifically set: forthiirthe follow- Because the vehicle is miscible with water and tissue fluid, products formed by the processes of this invention are free from the undesirable characteristics of oil solutions of androgenic ma terials. This means particularly: (a) freedom I from any danger of oil embolism, '.(b).freedom r from: any. effect'of oil on the rate of physiological :absorption; and (0): freedom from contamination of: syringe, sterilizer and accessory equipment with difficultly removable'oil or grease.

Products prepared by the processes of. thisinvention are obviously free from the disadvantages associated with pellet implantation. Being true solutions, these products 1 are administered by 5 means. of. a hypodermic syringe thus eliminating "-theineedfor unusual skill. on the partof. the operator forthe'preparation of a pe'lletcavity,: and fthus also avoiding exposing the patient to the risk oft..ihfeotioni associated with .the preparation of rsu'ch a cavity. 1'. Furthermorathe tendency toward pellet encapsulationis eliminated since the pre- J 'cipitated. particlesare relatively smalllin' size and faredistributed'throughout local tissues near the site-of injection.

ilBecause theyare' truesolutions at the time orth'eir preparation and administration, .the productsprepared' by the'proce'sses of .ithis invention 1. are? free from the disadvantages common to sus- "pension types of products. 'llo'precautionsineed be taken to assure uniform and'properparticle size. .No danger of contamination with foreign insoluble bodies exists because Ithe'products are 'true solutions and can be filtered by conventional processes torender them absolutely free of such "foreign bodies; furthermore, by virtue of the fact that the products are'true solutions, they can be subjected to the usual visual or physical: meth- -ods commonly employed in'the art for the'detection of such foreign materials. No difficulties *are'encountered'in the sterilization of products produced by the processes of this invention, either'filtration or heat sterilization methods beingadaptable'for the purpose without incurring the risk of causing any undesirable change in the products. The homogeneity of'the products produced by the processes of "this invention automatically-eliminates the need forprecautions on 5 the part of the technicianin order. toibecertain "that continuous doses withdrawnfromthe same multidose'container provide the same quantities of active ingredient.

Products formed by the: processes of thisinvention are superior to similarpreparations:consisting ofa' solution of the androgenic materialin'a puresolventin" various. respects. Properly pre-' "ples have been selected as typical members of groups of related substances which could be em- :ployed .in similar fashion. It is obvious that .thosawho arei skilled in the art of preparing parenteral medicinal products will recognize at .once that other agents can function in the place of those used in the examples, but recognition or the possibility of employing substitute materials shall in no way detract from or limit the broad claims of this invention.

Instead of testosterone, other androgenic materials such as testosterone esters and androgenic substances derived from various sterols by chemical processes may be employed.

The choice of solvents is not limited topropylene. glycol. Glycerin, or any other physiologically-inert, water-misciblesolvent may function in its placeprovided. that the androgenicmaterial is sufficiently soluble in'it and that saidan- .drogenic material will precipitate practically quantitatively when'the solution is diluted with an equal volume of physiological saline solution or tissue fiuid.

Similarly, although polyoxyalkylene sorbitan monolaurate is employed in the illustrativeexamples. as the. precipitation.regulator, actually the agent to be used for this purpose canbe selected from: a wide variety of chemical. compounds. ..It-is well recognized that both, physical and: chemical precipitation reactions'can often be controlled throughzthe inclusion of an additional .ingredientin. the reaction. mixture. in-

hibiting colloids such'as proteins and polysaccharides-can function in this manner. \SOTajISO can traces'of'fats, waxesfandhigh fatty acids and their related alcohols. Many of the synthetic organic detergents, emulsifying agents.

solubilizing agents, and surface active agents can also function as precipitationregulators; included among these are polyhydric alcohols and many of theirderivatives such as'their partial esters and their'polymeric condensation products. It is thus evident that there are very many agents which can function as precipitation regulators, and any of these which aretherapeutically-inert and do not otherwise confer undesirable characteristics on theproduct may be used in the processes'of this invention. I

1 Example No. 1

. Two grams of testosterone andQfive-tenths of one-gram of chlorobutanol, the bacteriostatic agent,.are dissolved in seventy seven and one-half .cubic centimetersof propyleneglycol with the aidof gentle. heat precautions being taken to .avoid volatilizationof the chlorobutanol. solution is complete, twentycubic centimeters of After water and two and. one-halfcubic centimeters oi polyoxyalkylene sorbitan monolaurate areadded.

The mixture is agitated and warmed if necessary until. solution. is again complete, after which it .is.sterilized by filtration under pressure and transferred aseptically into sterile containers "from which it is later withdrawn for therapeutic administration.

When one cubic centimeter or more of this solution is mixed with an equal volume of physiological sodium chloride solution, blood serum or tissue fluid, there results an immediate faint opalescence due to the commencement of precipitation of testosterone. As the testosterone continues to precipitate, the mixture acquires a deep white opacity and the colloidal particles of testosterone begin to coalesce into individually discernible masses interspersed by clear vehicle. Within five minutes after mixing, eighty five per cent or more of the total testosterone contained in the original sample has precipitated in the form of macroscopically uniform particles of dimensions suitable for therapeutic purposes.

Ewample No. .2

This differs from Example No. 1 with respect to the per cent of precipitation regulator present. The ingredients and quantities are the same as in Example No. 1 except that the quantity of polyoxyalkylene sorbitan monolaurate is increased to five cubic centimeters and that of the propylene glycol is reduced to seventy five cubic This differs from the preceding examples in that the per cent of precipitation regulator is still further increased. In this instance, ten cubic centimeters of polyoxyalkylene sorbitan monolaurate and seventy cubic centimeters of propylene glycol are employed, and the testosterone, chlorobutanol and water contents are kept the same as in the preceding examples. The compounding procedure remains the same as in the preceding examples.

When the solution of Example No. 3 is mixed with physiological sodium chloride solution, blood serum or tissue fluid, the same general phenomena are observed as described under Example No. 1 except that the times required for the initial and successive changes to take place are very noticeably and measurably increased beyond those observable in Example No. 2.

Example No. 4

This example is illustrative of the versatility of the processes of this invention with respect to sterilization of the final products. In the previous examples, a thermally unstable bacteriostatic agent, namely chlorobutanol, was employed, and hence sterilization of the nnal product was efiected by filtration. If for any reason a thermally stable bacteriostatic agent such as phenol or cresol is desired in the final product, such can also be accommodated in the processes of this invention through appropriate changes in the compounding procedure as described in the following.

The testosterone and the phenol or cresol are dissolved in the propylene glycol, and the water and polyoxyalkylene sorbitan monolaurate are added as in Example No. 1. The finished solution is then filtered and placed in the containers in which it is to be marketed. It may then be heat sterilized by any of several processes common to the industry.

I claim:

1. A clear solution for intramuscular administration in human therapy formulated to effect a substantially quantitative precipitation of its therapeutically active ingredient when injected, comprising an androgenic material selected from the group consisting of testosterone and testosterone esters, propylene glycol, water up to forty per cent, and approximately two and one-half to ten per cent of apolyoxyalkylene sorbitan fatty acid ester.

2. The composition of claim 1 containing a bacteriostatic agent.

3. A clear solution for intramuscular administration in human therapy formulated to effect a substantially quantitative precipitation of its therapeutically active ingredient when injected, consisting of two grams of testosterone, one-half gram of chlorobutanol, seventy seven and onehalf cubic centimeters of propylene glycol, twenty cubic centimeters of water, and two and one-half cubic centimeters of polyoxyalkylene sorbitan monolaurate.

CLARENCE T. VAN METER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,394,628 Meyer Feb. 12, 1946 2,417,299 Freedman Mar. 11, 1947 2,491,537 Welch Dec. 20, 1949 FOREIGN PATENTS Number Country Date 225,886 Switzerland June 16, 1943 433,938 Great Britain Aug. 23, 1935 434,406 Great Britain Aug. 30. 1935 515,566 Great Britain Dec. 8, 1939 555,445 Great Britain Aug. 24, 1943 OTHER REFERENCES Hamilton in Endocrinology, May 1939, 167/74 8, pages 711 to 719. 

1. A CLEAR SOLUTION FOR INTRAMUSCULAR ADMINISTRATION IN HUMAN THERAPY FORMULATED TO EFFECT A SUBSTANTIALLY QUANTITATIVE PRECIPITATION OF ITS THERAPEUTICALLY AN ANDROGENIC MATERIAL SELECTED FROM COMPRISING AN ANDROGENIC MATERIAL SELECTED FROM THE GROUP CONSISTING OF TESTOSTERONE AND TESTOSTERONE ESTERS, PROPYLENE GLYCOL, WATER UP TO FORTY PER CENT OF A POLYOXYALKLENE SORBITAN FATTY ACID ESTER. 